Autophagy impairment stimulates PS1 expression and γ-secretase activity

• Published in: Autophagy Vol. 6; no. 3; pp. 345 - 352
• Main Authors: Ohta, Kazunori, Mizuno, Akihito, Ueda, Masashi, Li, Shimo, Suzuki, Yoshihiro, Hida, Yoko, Hayakawa-Yano, Yoshika, Itoh, Masanori, Ohta, Eri, Kobori, Masuko, Nakagawa, Toshiyuki
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-04-2010
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - metabolism; Animals; Autophagy - physiology; Autophagy-Related Protein 5; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Line; Cycle; Gene Knockdown Techniques; Humans; Landes; Lysosomes - metabolism; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Organogenesis; Presenilin-1 - genetics; Presenilin-1 - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins
• ISSN: 1554-8627; 1554-8635
• DOI: 10.4161/auto.6.3.11228

γ-Secretase plays an important role in the development of Alzheimer disease (AD). γ-Secretase activity is enriched in autophagic vacuoles and it augments amyloid-β (Aβ) synthesis. Autophagy-lysosomal dysfunction has been implicated in AD, but whether γ-secretase activity is affected by autophagy remains unclear. Here we report that γ-secretase activity is enhanced in basal autophagy-disturbed cells through the α subunit of eukaryotic translation initiation factor 2 (eIF2α) kinase, general control nonderepressible 2 (GCN2). Presenilin-1 (PS1) expression was increased even in the presence of nutrients in autophagy-related 5 knockdown (Atg5
KD
) human embryonic kidney (HEK293) cells expressing a short hairpin RNA as well as in chloroquine-treated HEK293 cells. However, PS1 expression induction was prevented in GCN2
KD
and ATF4KD cells. Furthermore, Atg5KD cells showed an increase in Aβ production and Notch1 cleavage. These were reduced by an autophagy inducer, resveratrol. Thus, we conclude that the autophagy-lysosomal system regulates γ-secretase activity through GCN2.